title: Novel small-molecule inhibitors of Bcl-XL to treat lung cancer.
abstract: Bcl-XL is a major antiapoptotic protein in the Bcl-2 family whose overexpression is more widely observed in human lung cancer cells than that of Bcl-2, suggesting that Bcl-XL is more biologically relevant and therefore a better therapeutic target for lung cancer. Here, we screened small molecules that selectively target the BH3 domain (aa 90-98) binding pocket of Bcl-XL using the UCSF DOCK 6.1 program suite and the NCI chemical library database. We identified two new Bcl-XL inhibitors (BXI-61 and BXI-72) that exhibit selective toxicity against lung cancer cells compared with normal human bronchial epithelial cells. Fluorescence polarization assay reveals that BXI-61 and BXI-72 preferentially bind to Bcl-XL protein but not Bcl2, Bcl-w, Bfl-1/A1, or Mcl-1 in vitro with high binding affinities. Treatment of cells with BXI-72 results in disruption of Bcl-XL/Bak or Bcl-XL/Bax interaction, oligomerization of Bak, and cytochrome c release from mitochondria. Importantly, BXI-61 and BXI-72 exhibit more potent efficacy against human lung cancer than ABT-737 but less degree in platelet reduction in vivo. BXI-72 overcomes acquired radioresistance of lung cancer. On the basis of our findings, the development of BXI(s) as a new class of anticancer agents is warranted and represents a novel strategy for improving lung cancer outcome.
authors.affiliation: Departments of Radiation Oncology, Hematology and Medical Oncology, and Pathology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia, USA.
authors.forename: Dongkyoo
authors.initials: D
authors.lastname: Park
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Magis
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Taofeek K
authors.initials: TK
authors.lastname: Owonikoko
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Sica
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
mesh_terms: D000166:Acridines / Q000494:pharmacology*; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D045304:Cytochromes c / Q000378:metabolism; D005260:Female; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D055503:Protein Multimerization; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects*; D011839:Radiation, Ionizing; D054852:Small Molecule Libraries; D013449:Sulfonamides / Q000494:pharmacology*; D015996:Survival Rate; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C501332:ABT-737; D000166:Acridines; D000631:Aminopyridines; C494772:BAK1 protein, human; C584577:BXI-61; C584578:BXI-72; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D054852:Small Molecule Libraries; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051020:bcl-X Protein; D045304:Cytochromes c